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Expression of cyclin D2, P53, Rb and ATM cell cycle genes in brain tumors

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Abstract

Cyclin D2, P53, Rb and ATM as cell cycle genes regulate cell growth and proliferation. Considering their roles, we assumed that they have different level of mRNA expression in different grades of brain tumors. To determine this point, we investigated the mRNA expression in two types of brain tumors, including astrocytoma and meningioma. The mRNA of 52 brain tumor samples were extracted; cyclin D2, P53, Rb and ATM mRNA expression was quantified using the real-time quantitative reverse-transcription polymerase chain reaction. We compared mRNA expression of these genes between astrocytoma and meningioma tumors and also between different grades of them. Cyclin D2, P53, Rb and ATM had higher expression in astrocytoma than meningioma tumors. Higher grade (III and IV) of astrocytoma tumors had up-regulation for cyclin D2 and ATM genes, but higher grades of these tumors showed down-regulation of P53 and Rb genes. Analysis of relative expression between two grades of meningioma tumors showed a high down-regulation in grade II related to grade I. Also, cyclin D2, P53, Rb and ATM mRNA expression in each group of tumors (meningioma and astrocytoma) showed a highly positive correlation in lower grades. Considering this fact and also different templates of up- and down-regulation for these genes’ interaction in different types of brain tumors, it seems that these genes do not have a unique model of interaction.

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References

  1. Neufeld TP, Edgar BA. Connections between growth and the cell cycle. Curr Opin Cell Biol. 1998;10(6):784–90.

    Article  PubMed  CAS  Google Scholar 

  2. Sherr CJ. Mammalian G1 cyclins. Cell. 1993;73(6):1059–65.

    Article  PubMed  CAS  Google Scholar 

  3. Pines J. Cyclins and cyclin-dependent kinases: take your partners. Trends Biochem Sci. 1993;18(6):195–7.

    Article  PubMed  CAS  Google Scholar 

  4. Morgan DO. Principles of CDK regulation. Nature. 1995;374(66518):131–4.

    Article  PubMed  CAS  Google Scholar 

  5. Milde-Langosch K, Hagen M, Bamberger A-M, Löning T. Expression and prognostic value of the cell-cycle regulatory proteins, Rb, p16MTS1, p21WAF1, p27KIP1, cyclin E, and cyclin D2, in ovarian cancer. Int J Gynecol Pathol. 2003;122:168–74.

    Article  Google Scholar 

  6. Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999;13(12):1501–12.

    Article  PubMed  CAS  Google Scholar 

  7. Ekholm SV, Reed SI. Regulation of G1 cyclin-dependent kinases in the mammalian cell cycle. Curr Opin Cell Biol. 2000;12:676–84.

    Article  PubMed  CAS  Google Scholar 

  8. Evron E, Umbricht CB, Korz D, Raman V, Loeb DM, Niranjan B, et al. Loss of cyclin D2 expression in the majority of breast cancers is associated with promoter hypermethylation. Cancer Res. 2001;61(6):2782–7.

    PubMed  CAS  Google Scholar 

  9. Dey A, She H, Kim L, Boruch A, Guris DL, Carlberg K, et al. Colony-stimulating factor-1 receptor utilizes multiple signaling pathways to induce cyclin D2 expression. Mol Biol Cell. 2000;11:3835–48.

    PubMed  CAS  Google Scholar 

  10. Lee WH, Hollingsworth RE, Qian YW, Chen PL, Hong F. RB protein as a cellular ‘‘corral’’ for growth-promoting proteins. Cold Spring Harbor Symp Quant Biol. 1991;56:211–7.

    PubMed  CAS  Google Scholar 

  11. Weinberg RA. The retinoblastoma protein and cell cycle control. Cell. 1995;81:323–30.

    Article  PubMed  CAS  Google Scholar 

  12. Nevins JR, Leone G, Degregori J, Jakoi L. Role of the Rb/E2F pathway in cell growth control. J Cell Physiol. 1997;173:233–6.

    Article  PubMed  CAS  Google Scholar 

  13. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.

    Article  PubMed  CAS  Google Scholar 

  14. Lane DP. P53, guardian of the genome. Nature. 1992;358:15–6.

    Article  PubMed  CAS  Google Scholar 

  15. Pietenpol JA, Vogelstein B. Tumor suppressor genes. No room at the p53 inn. Nature. 1993;365:17–8.

    Article  PubMed  CAS  Google Scholar 

  16. Bardeesy N, Beckwith JB, Pelletier J. Clonal expansion and attenuated apoptosis in Wilms’ tumors are associated with p53 gene mutations. Cancer Res. 1995;55(2):215–9.

    PubMed  CAS  Google Scholar 

  17. Ginsberg K, Mechta F, Yaniv M. Wild type p53 can down-modulate the activity of various promotors. Proc Natl Acad Sci USA. 1991;88:9979–83.

    Article  PubMed  CAS  Google Scholar 

  18. Mack DH, Vartikar J, Pipas JM. Specific repression of TATA-mediated but not initiator-mediated transcription by wild-type p53. Nature. 1993;363:281–3.

    Article  PubMed  CAS  Google Scholar 

  19. Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997;88:323–31.

    Article  PubMed  CAS  Google Scholar 

  20. Deb S, Jackson CT, Subler MA. Modulation of cellular and viral promoters by mutant human p53 proteins found in tumor cells. J Virol. 1992;66:6164–70.

    PubMed  CAS  Google Scholar 

  21. Vogelstein B, Kinzler K. p53 function and dysfunction. Cell. 1992;70:523–6.

    Article  PubMed  CAS  Google Scholar 

  22. Ko LJ, Prives C. P53: puzzle and paradigm. Genes Dev. 1996;10:1054–72.

    Article  PubMed  CAS  Google Scholar 

  23. Baross A, Schertzer M, Zuyderduyn SD, Jones SJM, Marra MA, Lansdorp PM. Effect of TERT and ATM on gene expression profiles in human fibroblasts. Genes Chromosomes Cancer. 2004;39:298–310.

    Article  PubMed  CAS  Google Scholar 

  24. Meulmeester E, Pereg Y, Shiloh Y, Jochemsen AG. ATM-mediated phosphorylations inhibit Mdmx/Mdm2 stabilization. Cell Cycle. 2005;4(9):1166–70.

    Article  PubMed  CAS  Google Scholar 

  25. Stommel JM, Wahl GM. Accelerated MDM2 auto-degradation induced by DNA-damage kinases is required for p53 activation. EMBO J. 2004;23:1547–56.

    Article  PubMed  CAS  Google Scholar 

  26. Pereg Y, Shkedy D, Graaf Pd, Meulmeester E, Edelson-Averbukh M, Salek M, et al. Phosphorylation of Hdmx mediates its Hdm2- and ATM-dependent degradation in response to DNA damage. Proc Natl Acad Sci USA. 2005;102:5056–61.

    Article  PubMed  CAS  Google Scholar 

  27. Maya R, Balass M, Kim ST, Shkedy D, Leal JF, Shifman O, et al. ATM-dependent phosphorylation of Mdm2 on serine 395: Role in p53 activation by DNA damage. Genes Dev. 2001;15:1067–77.

    Article  PubMed  CAS  Google Scholar 

  28. Lavin MF, Birrell G, Chen P, Kozlov S, Scott S, Gueven N. ATM signaling and genomic stability in response to DNA damage. Mutat Res. 2005;569:123–32.

    PubMed  CAS  Google Scholar 

  29. Szabo CI, Schutte M, Broeks A. Are ATM mutations 7271T->G and IVS10–6T->G really high-risk breast cancer susceptibility alleles? Cancer Res. 2004;64:840–3.

    Article  PubMed  CAS  Google Scholar 

  30. Hall J. The ataxia-telangiectasia mutated gene and breast cancer: gene expression profiles and sequence variants. Cancer Lett. 2005;227(2):105–14.

    Article  PubMed  CAS  Google Scholar 

  31. Gutierrez-Enriquez S, Fernet M, Dork T. Functional consequences of ATM sequence variants for chromosomal radiosensitivity. Genes Chromosomes Cancer. 2004;40:109–19.

    Article  PubMed  CAS  Google Scholar 

  32. Waha A, Sturne C, Kessler A. Expression of the ATM gene is significantly reduced in sporadic breast carcinomas. Int J Cancer. 1998;78:306–9.

    Article  PubMed  Google Scholar 

  33. Kovalev S, Mateen A, Zaika AI, O’Hea BJ, Moll UM. Lack of defective expression of the ATM gene in sporadic breast cancer tissues and cell lines. Int J Oncol. 2000;16:825–31.

    PubMed  CAS  Google Scholar 

  34. Raptis S, Bapat B. Genetic instability in human tumors. EXS. 2006;96:303–20.

    PubMed  CAS  Google Scholar 

  35. Shiloh Y, Kastan MB. ATM: genome stability, neuronal development, and cancer cross paths. Adv Cancer Res. 2001;83:209–54.

    Article  PubMed  CAS  Google Scholar 

  36. Charames GS, Bapat B. Genomic instability and cancer. Curr Mol Med. 2003;3:589–96.

    Article  PubMed  CAS  Google Scholar 

  37. Lichtenstein A, Lichtenstein M, Lichtenstein D, Deborah, Lichtenstein E. http://voicesagainstbraincancer.org/Initiatives/RaiseYourVoiceProgram/2WhatisCancer/tabid/85/Default.aspx. 2009 March 26, 2009 [cited 2009 June 02].

  38. Tatter SB, Wilson CB, Harsh GRIV. Neuroepithelial tumors of the adult brain. 4th ed. Philadelphia: W.B. Saunders; 1995.

    Google Scholar 

  39. Kleihues P, Burger PC, Scheithauer BW. The new WHO classification of brain tumours. Brain Pathol. 1993;3(3):255–68.

    Article  PubMed  CAS  Google Scholar 

  40. Lukas J, Bartkova J, Welcker M, Petersen OW, Peters G, Strauss M, et al. Cyclin D2 is a moderately oscillating nucleoprotein required for G1 phase progression in specific cell types. Oncogene. 1995;10:2125–34.

    PubMed  CAS  Google Scholar 

  41. Sweeney KJ, Sarcevic B, Sutherland RL, Musgrove EA. Cyclin D2 activates Cdk2 in preference to Cdk4 in human breast epithelial cells. Oncogene. 1997;14(11):1329–40.

    Article  PubMed  CAS  Google Scholar 

  42. Sicinski P, Donaher JL, Geng Y, Parker SB, Gardner H, Park MY, et al. Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis. Nature (Lond). 1996;384:470–4.

    Article  CAS  Google Scholar 

  43. Yu J, Leung WK, Ng EK, To KF, Ebert MP, Go MY, et al. Effect of Helicobacter pylori eradication on expression of cyclin D2 and p27 in gastric intestinal metaplasia. Aliment Pharmacol Ther. 2001;15(9):1505–11.

    Article  Google Scholar 

  44. Takano Y, Kato Y, Masuda M, Ohshima Y, Okayasu I. Cyclin D2, but not cyclin D1, overexpression closely correlates with gastric cancer progression and prognosis. J Pathol. 1999;189:194–200.

    Article  PubMed  CAS  Google Scholar 

  45. Buckley MF, Sweeney KJ, Hamilton JA, Sini RL, Manning DL, Nicholson RI, et al. Expression and amplification of cyclin genes in human breast cancer. Oncogene. 1993;8:2127–33.

    PubMed  CAS  Google Scholar 

  46. Tam SW, Theodoras AM, Shay JW, Draetta GF, Pagano M. Differential expression and regulation of cyclin D1 protein in normal and tumor human cells: association with Cdk4 is required for cyclin D1 function in G1 progression. Oncogene. 1994;9:2663–74.

    PubMed  CAS  Google Scholar 

  47. Schmidt BA, Rose A, Steinhoff C, Strohmeyer T, Hartmann M, Ackermann R. Up-regulation of cyclin-dependent kinase 4/cyclin D2 expression but down-regulation of cyclin-dependent kinase 2/cyclin E in testicular germ cell tumors. Cancer Res. 2001;61:4214–21.

    PubMed  CAS  Google Scholar 

  48. Diccianni MB, Omura-Minamiawa M, Batova A, Le T, Bridgeman L, Yu AL. Frequent deregulation of p16 and the p16/G1 cell cycle-regulatory pathway in neurobalastoma. Int J Cancer. 1999;80:145–54.

    Article  PubMed  CAS  Google Scholar 

  49. Mukhopadhyay D, Tsiokas L, Sukhatme VP. Wild-type p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression. Cancer Res. 1995;55:6161–5.

    PubMed  CAS  Google Scholar 

  50. Hollstein M, Sidransky D, Vogelstein B. p53 mutation in human cancers. Science. 1991;253:49–53.

    Article  PubMed  CAS  Google Scholar 

  51. Quinlan DC, Davidson AS, Summers CL. Accumulation of p53 correlates with a poor prognosis in human lung cancers. Cancer Res. 1992;53:4828–31.

    Google Scholar 

  52. Fontanini G, Boldrini S, Vignati S. Bcl2 and p53 regulate vascular endothelial growth factor (VEGF)-mediated angiogenesis in non-small cell lung cancer. Eur J Cancer. 1998;34:718–23.

    Article  PubMed  CAS  Google Scholar 

  53. Maeda T, Matsumura S, Hiranuma H. Expression of vascular endothelial growth factor in human oral squamous cell carcinoma: its association with tumour progression and p53 gene status. J Clin Pathol. 1998;51:771–5.

    Article  PubMed  CAS  Google Scholar 

  54. Ambs S, Bennett WP, Merriam WG. Vascular endothelial growth factor and nitric oxide synthase expression in human lung cancer and the relation to p53. Br J Cancer. 1998;78(2):233–9.

    Article  PubMed  CAS  Google Scholar 

  55. Ye S, Zhong X, Chen Y. p53 and vascular endothelial growth factor expression in astrocytoma and their relation to angiogenesis. Zhonghua Zhong Liu Za Zhi. 2001;23(4):326–9.

    PubMed  CAS  Google Scholar 

  56. Danks RA, Chopra G, Gonzales MF, Orian JM, Kaye AH. Aberrant p53 expression does not correlate with the prognosis in anaplastic astrocytoma. Neurosurgery. 1995;37(2):246–54.

    Article  PubMed  CAS  Google Scholar 

  57. Malmer BS, Feychting M, Lönn S, Lindström S, nberg HG, Ahlbom A, et al. Genetic variation in p53 and ATM haplotypes and risk of glioma and meningioma. J Neurooncol. 2007;82:229–37.

    Article  PubMed  CAS  Google Scholar 

  58. Mehdipour P, Habibi L, Mohammadi-Asl J, Kamalian N, Azin MM. Three-hit hypothesis in astrocytoma: tracing the polymorphism D1853N in ATM gene through a pedigree of the proband affected with primary brain tumor. J Cancer Res Clin Oncol. 2008;134:1173–80.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Majid Kheirollahi & Parvin Mehdipour

  2. Department of Surgery, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran

    Masoud Mehr-Azin

  3. Department of Pathology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran

    Naser Kamalian

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  1. Majid Kheirollahi
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  2. Masoud Mehr-Azin
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Correspondence to Parvin Mehdipour.

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Kheirollahi, M., Mehr-Azin, M., Kamalian, N. et al. Expression of cyclin D2, P53, Rb and ATM cell cycle genes in brain tumors. Med Oncol 28, 7–14 (2011). https://doi.org/10.1007/s12032-009-9412-8

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